Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. We have developed sensitive DNA-based genotyping assays for detecting the at-risk genetic variants for enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Following testing of over 1000 individuals for these candidate susceptibility genes, we find that the frequency of the at-risk genotypes for glutathione transferase mu (GSTM1), n-acetyltransferase (NAT1 and NAT2) and aryl hydrocarbon hydroxylase (CYP1A1) vary significantly between Asians, Caucasian- and African-americans. Such variation suggests the possibility that some of the ethnic differences in cancer incidence may be due to genetic differences as well as exposure differences. In addition, we have genotyped ~1000 individuals in control and carcinogen-exposed populations and find that individuals with at-risk genotypes have higher levels of genotoxic damage (DNA adducts, HPRT mutation frequency, chromosome damage) in lymphocytes. Analysis of HPRT mutation frequency in smokers indicates that years of smoking, as well as current smoking, influences mutation damage. In collaboration with Jack Taylor, NIEHS we are testing the impact of these candidate cancer susceptibility genes in studies of bladder cancer, lung cancer and liver cancer. Individuals that carry the at-risk genotype for glutathione transferase mu, which detoxifies constituents of cigarette smoke, suffer a 70% increased risk of bladder cancer (p=0.004). In ongoing studies with researchers at the National Cancer Institute, Columbia University, University of North Carolina and University of Keele, England we are exploring how genetic variability in carcinogen metabolism affects risk for cancer of the bladder, lung, liver, gastric, colon, head and neck. These studies seek to integrate environmental and genetic factors in the development of human disease.